Cause of Celiac Disease

Wheat Flour Water Insoluble Fraction Gluten Starch Fat Fiber Protein Water Soluble Fraction Alcohol Insoluble Glutenin Alcohol Soluble Gliadin

Celiac Disease

Histopathology - prior to Tx  Flat biopsy with surface damage  Increased Intraepithelial lymphocytes  Increased lamina propria inflammation – Plasma cells  Increased crypt mitoses

Flat bx with lots of IELS – fully developed sprue-like changes

Note surface damage with lots of IELS

Activated T-cells in surface epithelium

Increased mitoses in the crypts

The mucosal thickness doesn’t change as there is crypt hyperplasia

Classification of Celiac Lesions Marsh 3A Marsh 3B Marsh 3C

Celiac Disease

Histopathology - Shortly after Tx  Marked clinical improvement  Surface epithelium restored  Slight return of villi  Other findings unchanged

Gluten Free Diet - 2 Weeks

Celiac Disease

Histopathology - Long term Tx  Continued clinical improvement  Further return of villi  Mitotic rate subsides  Chronic inflammation subsides

Villi are present but abnormal, hard to get all gluten out of diet

Better but not normal histology still eating some gluten??

Celiac Disease Gluten Challenge  Epithelial lymphocytes increase  Epithelial damage to upper villi  Full-blown lesion develops later

Celiac Disease Pathogenic Factors

 Genetic Aspects – Familial Occurrence (11-22% first degree relative) – Identical Twin Concordance (70%) – HLA Associations ( DQ2, B8)  Environmental Factors – Dietary Gluten – Twin non-concordance rate of 30%; separate onsets – ?Viral exposure (Adenovirus type 12)

Protein Sequence Homology

adenovirus type 12 induces molecular mimicry due to homology?

Serologic Markers In Celiac Disease Marker Anti-gliadin Anti-reticulin Anti-endomysium Tissue Transglut Sensitivity 31-100% 42-100% 60-100% 85-100% Specificity 85-100% 95-100% 95-100% 92-97%

Ugh - immunology Schuppan D. Gastroenterol 2000:119;234-242

Schuppan et al. Gastro 2009;137:1912-33 Pinier et al, Am J Gastroenterol 105:2551-2561;2010

Normal on the right versus too many IELS on the left This is the Marsh 1 lesion

Marsh 1 = Nl villi with too many IELs

How many IELs are abnormal?

 >25/100 epithelial cells – new threshold for flat biopsies  >40/100 epithelial cells – old threshold for flat biopsies  >12/20 epithelial cells on the tips of villi (for Marsh 1) – Decrescendo pattern is normal – Diffuse pattern is abnormal – Goldstein Am J Clin Pathol 116;63-71,2001  >8/20 epithelial cells in the tips of villi (for Marsh 1) – CD3 stains – Biagi et al J Clin Pathol 57;835-839, 2004

CD3 stain highlighting a Marsh 1 lesion Don’t get this stain unless you are used to what it looks like in a normal biopsy!

But what does it all mean?

 2-3 % of small bowel biopsies have normal architecture with increased IELs  Depending on the type of study and the country the study was carried out in, anywhere from 9 to 40% of such cases represent (pre) celiac disease.

– Whether such patients need any therapy is controversial Brown I,et al. Arch Pathol Lab Med 130;1020-25, 2006

Normal Architecture Increased IELs          Gluten Sensitive Enteropathy – Early type 1 lesion or treated sprue Other food hypersensitivity H. Pylori (usually only in bulb) Autoimmune conditions (RA, SLE, MS, Graves, Hashimoto ’ s, Diabetes) Post-infection Drugs (NSAIDs, PPIs??) Bacterial Overgrowth Obesity Crohn ’ s disease and Ulcerative colitis

H. pylori, 7 IBS, 9 Other, 7 Bacterial Overgrowth, 7 Crohn's, 7 NSAID, 17 CD, 19 Idiopathic, 31 Other Diagnoses: Graft versus Host Disease, Combined Variable Immunodeficiency, Diabetes mellitus 1, Juvenile Rheumatoid Arthritis, Systemic Lupus Erythematosis, Tropical Sprue, Ulcerative Colitis

Celiac Disease Complications

 Refractory Celiac Disease  Ulcers of Small Bowel  Collagenous Sprue  Malignancy – T cell Lymphoma of gut and regional nodes – Adenocarcinoma of small bowel – Squamous cell carcinoma of esophagus and oropharynx

Refractory Celiac Disease

 Develops in about 5% of celiac patients – Malabsorption, diarrhea, pain, wt loss  Divided into types I and II  Type I RCD: IELs are normal / not clonal – better prognosis – Can progress to Type II  Type II RCD: IELs are aberrant / clonal – 50% mortality rate

Refractory Celiac Disease

 IELs in Celiac disease and type I RCD are CD3 + and CD8 +  IELs in type II RCD are CD3 + and CD8 – Will have T-cell gene rearrangements – Will also loose staining for T-cell receptor αβ

Loss of CD8 in type 2 refractory sprue CD3 CD8

Collagenous Sprue

Collagenous Sprue

LYMPHOMA IN CELIAC DISEASE

EATCL with lots of eos

Malabsorption Sprue-like Changes Remain Well Benign Ulcer Response Gluten Free Diet No Response (Refractory Sprue) Deterioration Refractory Celiac Disease Lymphoma

Celiac Disease Histologic Mimics  Celiac-related – Lymphoma (EATCL) – Collagenous Sprue  Other luminal antigens other than gluten/gliadin – Soy protein  General – Peptic duodenitis* = most commonly mis dxed as sprue – Tropical Sprue, Bacterial overgrowth – Autoimmune enteropathy – Infections/immunodeficiencies – Crohn ’ s disease

Looks like sprue, but this is peptic duodenitis – no IELs

Peptic Duodenitis with polys instead of IELS

More peptic duodenitis Note gastric metaplasia